KSQ-4279 / KSQ Therapeutics - LARVOL DELTA

First-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations. (ASCO 2024) - P1 | "KSQi is a first-in-class USP1 inhibitor with an acceptable safety profile as SA and in combination. An MTD was not reached in any Arms. PD results support the mechanism of action of USP1 inhibition."

Clinical • Combination therapy • Metastases • P1 data • Anemia • Cardiovascular • Fallopian Tube Cancer • Heart Failure • Hematological Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • HRD • PCNA • USP1

REVEALING THERAPEUTIC VULNERABILITY IN HIGHLY CHEMORESISTANT TCF3::HLF B-ALL: GENOME-WIDE CRISPR/CAS9 SCREENING IDENTIFIES CRITICAL MOLECULAR DETERMINANTS OF RESPONSE TO THE NEW PRODRUG ACHM-025 (EHA 2026) - "Furthermore, pharmacological inhibition of USP1 phenocopied the genetic loss, where treatment with the selective inhibitor KSQ-4279 demonstrated synergistic activity in combination with ACHM-025 in UoC-B1 cells...The observed synergy between ACHM-025 and USP1 inhibition supports a rational combination strategy to enhance anti-leukaemic efficacy in this fatal subtype. ACHM-025 is currently being evaluated in vivo using a single mouse trial (SMT) format across 15 independent TCF3::HLF PDX samples."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • AKR1C3 • ARID2 • SUV39H1 • TBL1XR1 • TCF3 • USP1

Design and Synthesis of USP1 Inhibitors: Synergistic Antitumor Activity with PARP Inhibitors in Triple-Negative Breast Cancer. (PubMed, J Med Chem) - "Guided by USP1-UAF1 structural insights, we optimized the KSQ-4279 scaffold and identified 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one as a scaffold-hopping core for proof-of-concept exploration...In vitro assays and in vivo xenograft studies demonstrated synergistic antitumor activity between compound 57 and Olaparib, resulting in DNA damage and significantly enhanced tumor growth inhibition compared with Olaparib monotherapy. Transcriptomic analysis and Western blot results further supported enhanced suppression of tumor survival pathways. Collectively, this work establishes compound 57 as a scaffold-hopping, proof-of-concept USP1 inhibitor and provides in vivo validation for USP1-PARP inhibitor combination therapy in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • PCNA • USP1

Discovery of a Potent Fluorescence Polarization Probe for Identifying USP1 Allosteric Inhibitors. (PubMed, Adv Sci (Weinh)) - "In addition, a novel class of potent tetrahydroisoquinoline USP1 inhibitors was identified, and the representative compound 14a possessed superior enzymatic and cellular activity compared with the clinical candidate KSQ-4279, with potent in vivo anti-DLBCL efficacy and good druggability. Collectively, this study provides a valuable fluoroprobe, FP assay platform, and lead compounds targeting USP1 for further structural optimization and antitumor mechanism studies."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Targeted Protein Degradation • USP1

Small molecule inhibitor of FEN1 nuclease utilizing a novel metal-binding pharmacophore synergizes with inhibitors of USP1, PARP, PARG and ATR (AACR 2024) - "Synergistic relationships of BSM-1516 and its combination potential were further explored in viability studies with a panel of DDR inhibitors (n=25) in BRCA2-proficient and deficient cell lines. Strong synergy was identified with multiple drug classes that included inhibitors of USP1 (KSQ-4279), PARP (Olaparib, Niraparib, Talazoparib, AZD5305), PARG (PDD 00017273) and ATR (AZD6738, VE-822, Elimusertib).In vitro ADME assays and in vivo PK studies showed that BSM-1516 has properties suitable for in vivo testing, either as a single agent or in combination with synergistic DDR inhibitors, an investigation that is currently underway."

Oncology • BRCA2 • FEN1 • RPA2 • USP1

ASN-3186 is a potent and selective inhibitor of USP1 for the treatment of BRCA1/2 mut and HRD+ cancers (AACR 2024) - "MDA-MB-436 CDX mouse model confirmed dose-dependent, single-agent inhibitory activity of ASN-3186 in vivo with higher potency than KSQ4279, possibly due to ASN-3186's higher oral bioavailability...The combination of ASN-3186 and PARPi Olaparib yielded a more robust and durable anti-tumor response, with near-complete tumor regression demonstrated at higher combination dose...Synthetic lethal activity was also observed when ASN-3186 was combined with DNA damage drug Gemcitabine. Furthermore, ASN-3186 displayed desirable ADME and PK profiles with high oral bioavailabilities (>75%) across species. These data support further clinical development of ASN-3186 as a potential best-in-class USP1 inhibitor, both as a single agent as well as in combination with PARPi, for treatment of BRCA1/2 mut and HRD+ cancers."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • BRCA2 • HRD • PCNA • USP1

Activity of PARP1-selective inhibitor SNV-001 in models of HRD cancers as monotherapy and in combination (AACR 2024) - "SNV-001 showed greater efficacy at lower doses compared to olaparib at 100 mg/kg or at equivalent doses of AZD9574...SNV-001 enhanced cytotoxicity of the DNA-damaging agent topotecan or carboplatin in Capan-1 (BRCA2mut) and HCC1395 (BRCA1mut) cells. Synergy was seen between SNV-001 and cell cycle check point inhibitors camonsertib (ATRi) or adavosertib (WEE1i) in DLD1 (BRCA2 -/-) and UWB1.289 (BRCA1mut) cells, as DNA damage induced by PARP1 trapping relies on cell cycle modulation for repair. Combination of SNV-001 with polymerase theta inhibitor ART558 or USP1 inhibitor KSQ4279 exhibited synergistic effects in DLD1 (BRCA2 -/-) or UWB1.289 (BRCA1mut) cells...Current data highlight a potential strategy for improving treatment efficacy and overcoming resistance. Further clinical investigations are warranted to validate this combination strategy."

Monotherapy • Oncology • BRCA1 • BRCA2 • HRD • PARP2 • USP1

VRN19: A novel USP1 Inhibitor with anti-tumor efficacy and favorable safety profile (AACR 2025) - "In the BRCA1-mutated CDX model (MDA-MB-436) and PDX with resistance to PARP inhibitors, VRN19 demonstrated synergistic effect with PARP inhibitors, particularly with olaparib, and showed efficacy comparable to KSQ-4279 without toxicity. In a 2-week toxicity study in rats, administration of 300 mg/kg VRN19 showed no significant changes in anemia markers, such as RBC, Hb, and reticulocytes, nor hepatotoxicity indicators like GGT and bilirubin. However, administration of 300 mg/kg KSQ-4279 significantly elevated anemia-related markers and GGT levels, consistent with the adverse events observed in clinical trials with KSQ-4279.In conclusion, VRN19 is a promising novel USP1 inhibitor with favorable safety and improved therapeutic outcomes."

Clinical • Late-breaking abstract • Oncology • BRCA • BRCA1 • BRCA2 • USP1

Synergistic tumor cell killing with dual inhibition of PARG and USP1 (AACR 2025) - "Interestingly, a CRISPR screen with USP1 inhibitor (USP1i) KSQ-4279 has identified gRNAs against genes encoding proteins in the OFP and base excision repair (BER) pathways, particularly PARG and PARP1, as key sensitizers...Our data provides novel mechanistic insights into the therapeutic potential of combining these inhibitors, offering preclinical evidence to support its advancement for treating tumors with HRD and those resistant to PARP inhibitors. This combination strategy holds promise for enhancing treatment efficacy while reducing toxicity, paving the way for more targeted and effective therapeutic options."

Tumor cell • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • HRD • USP1

Insilco evaluation of multiple ubiquitin-specific protease 1 (USP1) inhibitors and selectivity profiling over other USPs using Alphafold (AACR 2025) - "Here, we used USP1 crystal structures (PDB: 7ZH4 and 9FCJ) to study the comparison of multiple novel USP1 inhibitors alongside the clinical USP1 inhibitor KSQ-4279 and a well-established tool compound, ML323...Our results advance the in silico understanding of the binding modes of these novel ligands and underscore their selective potential. We aim to utilize this data for the design of new USP1 inhibitors."

Oncology • USP1

KSQ-4279-1101: A Phase 1 Study of RO7623066 Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=116 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | N=250 ➔ 116

Enrollment change • Trial completion • Solid Tumor

Discovery and Optimization of Novel Tricyclic Ubiquitin-Specific Protease 1 Inhibitors for the Treatment of BRCA-Mutated Breast Cancer. (PubMed, J Med Chem) - "Supported by its favorable pharmacokinetic properties, compound 43 exhibited significant in vivo anticancer efficacy in an MDA-MB-436 xenograft model, achieving superior tumor growth inhibition both as monotherapy and in combination with Olaparib compared to KSQ-4279. Collectively, compound 43 emerges as a promising preclinical candidate with translational potential for BRCA-mutated breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRCA • PCNA • USP1

KSQ-4279, an Inhibitor of Ubiquitin Specific Peptidase 1, Enhanced the Chemotherapeutic Efficacy in ABCB1/ABCG2/ABCC1-Mediated Multidrug Resistant Cancers. (PubMed, MedComm (2020)) - "Besides, at the effective reversal concentrations, KSQ-4279 neither altered expression and localization of ABCB1/ABCG2/ABCC1, nor affected USP1's potential downstream AKT or ERK1/2 signaling. This is the first study to investigate the combination of USP1 inhibitor (KSQ-4279) with traditional chemotherapeutic drugs in reversing MDR, which surprisingly hinted ABCB1, ABCG2, and ABCC1 as the new targets of KSQ-4279, and advocated this promising combination therapy in clinical refractory MDR cancers."

Journal • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ABCB1 • ABCC1 • ABCG2 • USP1

KSQ-4279-1101: A Phase 1 Study of RO7623066 Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=250 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2026 ➔ Nov 2025

Enrollment closed • Trial completion date • Solid Tumor

USP1 inhibition: A journey from target discovery to clinical translation. (PubMed, Pharmacol Ther) - "RO7623066 (KSQ-4279) reported an acceptable safety profile during a phase I dose escalation study, with anemia being the most common side effect, and demonstrated robust pharmacokinetic, pharmacodynamic, and clinical activity. Other USP1 inhibitors, including SIM0501, XL309-101, and HSK39775, are currently in early clinical development. In this review, we provide an overview of the molecular function of USP1 and its importance as a therapeutic target in oncology, before focusing on the current state of preclinical and clinical development of USP1 inhibitors."

Journal • Review • Hematological Disorders • Oncology • Targeted Protein Degradation • BRCA1 • FANCD2 • FANCI • PCNA • USP1

KSQ-4279-1101: A Phase 1 Study of RO7623066 Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=250 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2027 ➔ Jun 2026 | Trial primary completion date: Jun 2026 ➔ Aug 2025

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Discovery and Optimization of a Series of Novel Morpholine-Containing USP1 Inhibitors. (PubMed, J Med Chem) - "Herein, we utilized ring-opening and cyclization strategies based on KSQ-4279 to design a novel series of USP1 inhibitors featuring a morpholine scaffold...Importantly, it enhanced the sensitivity of olaparib-resistant cells to olaparib and showed a synergetic effect with andrographolide in BRCA-proficient cancer cells...In the MDA-MB-436 xenograft model, 38-P2 displayed significant, dose-dependent antitumor efficacy. Overall, these findings indicate that 38-P2 is a promising lead compound for further drug development."

Journal • Oncology • Targeted Protein Degradation • BRCA • USP1

The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination-Deficient Tumors. (PubMed, Cancer Res) - "These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials. Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor-resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors."

Journal • Oncology • Targeted Protein Degradation • BRCA • BRCA1 • BRCA2 • HRD • USP1

Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279. (PubMed, J Med Chem) - "Inhibitor binding drives a substantial increase in thermal stability of USP1, which may be mediated through the inhibitors filling a hydrophobic tunnel-like pocket in USP1. Our results contribute to the understanding of the mechanism of action of USP1 inhibitors at the molecular level."

Journal • Oncology • Targeted Protein Degradation • USP1

KSQ-4279-1101: A Phase 1 Study of RO7623066 Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=250 | Recruiting | Sponsor: Hoffmann-La Roche | N=140 ➔ 250

Enrollment change • Metastases • Oncology • Solid Tumor

Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors. (PubMed, Eur J Med Chem) - "In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors."

Journal • Breast Cancer • Oncology • Solid Tumor • USP1

KSQ-4279-1101: A Phase 1 Study of RO7623066 Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=140 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Feb 2025 ➔ Jun 2027 | Trial primary completion date: Jun 2024 ➔ Jun 2026

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

A Phase 1 Study of KSQ-4279 Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=140 | Recruiting | Sponsor: KSQ Therapeutics, Inc. | Active, not recruiting ➔ Recruiting | N=64 ➔ 140

Enrollment change • Enrollment open • Metastases • Oncology • Solid Tumor

A Phase 1 Study of KSQ-4279 Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=64 | Active, not recruiting | Sponsor: KSQ Therapeutics, Inc. | Recruiting ➔ Active, not recruiting | N=140 ➔ 64

Enrollment change • Enrollment closed • Metastases • Oncology • Solid Tumor

KSQ Therapeutics Enters Worldwide License Agreement with Roche for KSQ-4279, a Clinical-Stage USP1 Inhibitor for Cancer (Businesswire) - "KSQ Therapeutics, Inc...announced today it has entered into a worldwide license and collaboration agreement with Roche for the development and commercialization of KSQ-4279....Under the collaboration, Roche will assume development responsibilities for KSQ-4279, which has the potential to treat a variety of cancers....Under the terms of the agreement, KSQ will receive an upfront payment and will be eligible to receive additional milestone and royalty payments. KSQ grants Roche a global license wherein Roche will be fully responsible for the further development of KSQ-4279 in 2024."

Licensing / partnership • Breast Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer